In cancer cells multiple oncogenic lesions cooperate in malignant transformation. Such cooperation permits survival and proliferation of tumor cells in absence of contact with extra-cellular matrix (ECM), suggesting that tumor cell survival and proliferation have become independent of the engagement of integrin signaling by ECM.
Carcinogenesis is caused by multiple cooperating genetic lesions leading to a progressive deregulation of cellular signaling and cell cycle restriction point control. The mutations involved result in oncogene activation or loss of tumor-suppressor gene function. Typically, single oncogenes are insufficient to cause malignant transformation because they simultaneously induce signals stimulating and inhibiting cell growth. As a result cell proliferation remains restricted. In contrast, cooperating oncogenic lesions act in concert to disable such inhibitory signals while reinforcing the growth-promoting stimuli. The co-operation of oncogenic lesions involves integration of multiple signals converging on the regulation of cell cycle-dependent kinase complexes (Lloyd et al., 1997; Perez-Roger et al., 1999; Roper et al., 2001; Sewing et al., 1997).
Disclosed herein are compositions and methods that show survival of various transformed cell types requires cell-autonomous (autocrine) integrin signaling activity. This activity is induced by cooperating oncogenic lesions and involves induction of integrin receptor and ligand components such as integrin alpha6 and integrin beta4, and laminin5-gamma2 chains. Blocking of integrin or the laminin ligand function induces rapid apoptosis of the transformed cells, even when growing in presence of ECM. In contrast, normal cells remain viable when exposed to the same treatment.
The disclosed compositions and methods are related to the cooperation of oncogenic lesions controlling the ability of transformed cells to proliferate in the absence of contact with the extra-cellular matrix (ECM). As taught herein, oncogenes cooperate to promote a cell-autonomous (autocrine) integrin signaling loop that proves essential for the survival of various transformed cell types. As this signaling loop is not established in corresponding normal cells, the signaling components of this loop constitute attractive targets for cancer therapy.